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PubMed1980

Antitumor activity of 7-N-phenyl derivatives of mitomycin C in the leukemia P388 system.

The antitumor activity of 7-N-phenyl derivatives of mitomycin C was tested in an ip-ip system of mouse leukemia P388 by single administration. The compounds tested were 7-N-phenyl-, 7-N-(p-aminophenyl)-, 7-N-(p-hydroxyphenyl)- and 7-N-(p-chlorophenyl)-mitomycin C. The maximum increases in life span (ILSmax) obtained were 124, 169, > 386 and 112%, respectively, that with mitomycin C being 104%. 7-N-(p-Hydroxyphenyl)-mitomycin C showed a higher ILS% than its ortho and meta isomers. Thus, 7-N-(p-hydroxyphenyl)-mitomycin C was the most effective of these compounds.

Animals↗
PubMed1993

Induction of protein-DNA complexes in HeLa S3 cells by KW-2149, a new derivative of mitomycin C.

KW-2149 is a new water-soluble analogue of mitomycin C which shows a broad spectrum antitumor activity in experimental tumor models including mitomycin C-resistant tumors and is less hematotoxic than mitomycin C. We have found that KW-2149 increases protein-DNA complexes in HeLa S3 cells using the potassium/sodium dodecyl sulfate precipitation method which recovers largely DNA bound covalently to protein but does not precipitate DNA bound noncovalently to proteins. In contrast, no increase of the protein-DNA complexes are shown in cells treated with mitomycin C. Thus, KW-2149 binds covalently with both DNA and protein, and this may mediate for KW-2149 the potent and characteristic antitumor activity compared with mitomycin C.

Antineoplastic Agents↗
PubMedDate not supplied

Topical mitomycin C in the prevention of keloid scar recurrence.

OBJECTIVE: To assess the ability of mitomycin C to prevent the recurrence of surgically excised keloid scars. Mitomycin C has been successfully used to prevent scar tissue formation at the site of subglottic stenosis in the field of pediatric otolaryngology. It appears that mitomycin C interferes with the ability of fibroblasts to produce a scar without causing changes in epithelialization. DESIGN: We excised keloid scars from various sites in the head and neck and then applied mitomycin C to the resected bed prior to closure of the wound at a concentration of 0.4 mg/mL for 5 minutes. All patients had multiple keloids and acted as their own control. At 1 month after the procedure both wounds were started on a regimen of triamcinolone acetonide, 40 mg/mL injections, repeated every month for 6 months. At the end of the study, photos and measurements were again taken. RESULTS: Fifteen patients (13 female and 2 male) ranging in age from 10 to 55 years enrolled in the study. No infections or nonhealing wounds were seen. There was no difference in postoperative pain. Eight patients completed the triamcinolone injections, 5 had fewer than 6 injections, and 2 patients had no steroid injections. Twelve patients completed follow-up and were evaluated for surgical complications and recurrence of the keloids at either site. Two patients had partial postoperative follow-up in person and then completed follow-up via telephone. One patient could not be found for follow-up. Four patients had recurrence of both excised lesions. Ten patients had no recurrence of their keloids at either site. CONCLUSION: Mitomycin C made no difference in the prevention of keloid recurrence after excision when topically applied.

Administration, Topical↗
PubMed1991

Trabeculectomy with mitomycin. A comparative study with fluorouracil.

We conducted a prospective, randomized study to compare mitomycin with fluorouracil for efficacy and safety as an adjunct to trabeculectomy in eyes with glaucoma with poor surgical prognosis. Thirty-two eyes of 32 patients were randomly allocated to either mitomycin (17 eyes) or fluorouracil therapy (15 eyes). Mitomycin (0.2 mg) was applied only once during trabeculectomy, and fluorouracil (5 mg) was subconjunctivally injected 10 times in the 2 weeks after surgery. Fifteen eyes (88%) in the mitomycin group and seven (47%) in the fluorouracil group achieved an intraocular pressure of less than or equal to 20 mm Hg without antiglaucoma medication. The follow-up period was 7 to 12 months. Corneal complications were less common in the group given mitomycin than in that given fluorouracil (12% vs 53%). The incidence of other complications was similar between the two groups.

Adult↗
PubMed1991

The effects of subconjunctival mitomycin-C on glaucoma filtration surgery in rabbits.

A prospective, randomized, masked, placebo-controlled study was performed to determine whether a single, intraoperative subconjunctival application of a 0.5-mg/mL solution of mitomycin-C enhances the success of full-thickness filtration surgery in rabbits. Compared with control eyes, mitomycin-C-treated eyes showed significant increases in bleb duration from 8.1 +/- 2.4 to 68.0 +/- 20.8 days and in intraocular pressure reduction from 6.0 +/- 3.0 to 63.6 +/- 21.5 days. Histopathologic evaluation confirmed the inhibitory effects of mitomycin-C on fibrovascular, fibrocellular, and collagenous organization of the filtering blebs that resulted in their preservation. Transient, superficial, corneal vascularization anterior to the bleb occurred in all mitomycin-C-treated eyes. No other clinical or pathologic signs of undesirable side effects were noted. We studied the effectiveness and safety of a single intraoperative application of mitomycin-C in prolonging the success of filtration surgery in rabbits and its potential for similar use in humans.

Administration, Topical↗
PubMed1995

Decrease of intraocular pressure after subconjunctival injection of mitomycin in human glaucoma.

OBJECTIVE: To investigate the effects of a subconjunctival injection of mitomycin on the intraocular pressure in human eyes affected by glaucoma. DESIGN: Consecutive case series, prospective study, intraocular pairwise comparison (paired samples Student's t test adopted). SETTING: Hospital-based glaucoma clinic. PATIENTS: Twelve consecutive patients with bilateral glaucoma and monolateral blindness, intraocular pressure greater than 30 mm Hg in the blind eye (mean of the two highest values of the diurnal curve, confirmed at 96-hour interval), and no previous bulbar surgery. INTERVENTION: Subconjunctival injection of 0.5 mL of 0.2% mitomycin in the upper temporal quadrant, preceded and followed by treatment with topical indomethacin. MAIN OUTCOME MEASURE: Analysis of the variance of the mean intraocular pressure before and after the injection of mitomycin in each eligible eye. RESULTS: An intraocular pressure decrease was observed in each eligible eye the day after the treatment (mean [+/- SD] decrease, 7.15 +/- 1.46 mm Hg). The effect was still detectable at the end of the 60 days of follow-up (mean [+/- SD] decrease, 5.67 +/- 1.61 mm Hg). No change of intraocular pressure, in the meantime, was observed in the fellow eye. CONCLUSIONS: Topically applied mitomycin induces a decrease of intraocular pressure in human glaucomatous eyes. Our data confirm previous results obtained in albino rabbits and support the hypothesis that mitomycin exerts a still unknown direct effect on aqueous humor dynamics in the eye.

Adult↗
PubMed2003

Intravesical bacillus Calmette-Guerin versus mitomycin C for Ta and T1 bladder cancer.

BACKGROUND: Tumour recurrence following transurethral resection (TUR) for Ta and T1 bladder cancer is a major clinical problem. Intravesical administration of mitomycin C (MMC) or bacillus Calmette-Guerin (BCG) has proven prophylactic activity but both are associated with local and systemic side-effects. A systematic review was carried out to compare the efficacy of these two agents. OBJECTIVES: To undertake a systematic review and meta-analysis comparing intravesical mitomycin C and Bacillus Calmette-Guerin in terms of tumour recurrence, disease progression and overall survival in Ta and T1 bladder cancer. Treatment-related toxicities would also be evaluated. SEARCH STRATEGY: A comprehensive search of MEDLINE, EMBASE, Healthstar, Cochrane Controlled Trials Register, Cancerlit, and DARE was performed, and hand searching of relevant journals undertaken. SELECTION CRITERIA: Trials in any language were included in the meta-analysis if they were properly randomised, included medium to high risk patients with Ta or T1 bladder cancer and compared intravesical MMC versus BCG. DATA COLLECTION AND ANALYSIS: Trial eligibility, methodological quality and data extraction were assessed independently by two reviewers. Time to event analysis was evaluated using log hazard ratios, with a sensitivity analysis for subgroups according to patient's risk of recurrence. MAIN RESULTS: Twenty-five articles were identified but only seven were considered eligible. This represented 1901 evaluable patients in total, 820 randomised to MMC and 1081 to BCG. Six trials had sufficient data for meta-analysis and included 1527 patients, 693 in the mitomycin arm and 834 in the BCG arm. The weighted mean log hazard ratio (variance) for tumour recurrence for the six trials was - 0.022 (0.005). This indicated no significant difference between MMC and BCG (p = 0.76). However, the meta-analysis indicated evidence of significant heterogeneity between trials (p = 0.001). A subgroup analysis of three trials that included only high risk Ta and T1 patients indicated no heterogeneity (p = 0.25) and a log hazard ratio (variance) for recurrence of -0.371 ( 0.012). With MMC used as the control in the meta-analysis, a negative ratio is in favour of BCG and, in this case, is highly significant (p = 0.0008). The seventh trial, in abstract form only, used BCG in low doses for two arms of the trial (27 mg and 13.5mg) compared to a standard dose of mitomycin C (30mg), and reported a significantly reduced recurrent rate with BCG (27mg) compared to mitomycin C (p = 0.001). Only two trials included sufficient data to analyse disease progression and survival, representing a total of 681 patients; 338 randomised to BCG and 343 to MMC. There was no significant difference between MMC and BCG for disease progression (log hazard ratio + variance: 0.044 + 0.04, p = 0.16) or survival (-0.112 + 0.03, p = 0.50). Local toxicities (dysuria, cystitis, frequency, and haematuria) were associated with both MMC (30%) and BCG (44%). Systemic toxicities, such as chills, fever and malaise, were observed with both MMC and BCG (12% and 19%, respectively) although skin rash was more common with MMC. REVIEWER'S CONCLUSIONS: The data from the present meta-analysis indicate that tumour recurrence was significantly reduced with intravesical BCG compared to MMC only in the subgroup of patients at high risk of tumour recurrence. However, there was no difference in terms of disease progression or survival, and the decision to use either agent might be based on adverse events and cost.

Administration, Intravesical↗
PubMed1994

Unusually marked hypoxic sensitization to indoloquinone EO9 and mitomycin C in a human colon-tumour cell line that lacks DT-diaphorase activity.

Studies with purified DT-diaphorase have shown that the enzyme is capable of catalyzing a two-electron reduction of the novel indoloquinone EO9 to a DNA-damaging alkylating species. The aim of this study was to determine to what extent DT-diaphorase may be involved in the metabolic activation of EO9 and mitomycin C in both aerobic and hypoxic conditions. Two human colon-carcinoma cell lines were used; HT29 has high levels of DT-diaphorase whilst BE lacks this activity because of a point mutation in the NQOI gene. In aerobic conditions the 2 cell lines show similar sensitivities to a number of cytotoxic drugs including cisplatin, doxorubicin and etoposide. They are equally sensitive to the benzotriazine di-N-oxide SR 4233 but HT29 is more sensitive than BE to mitomycin C and EO9. Sensitivity to SR 4233 is increased by about 100-fold for both cell lines in hypoxic conditions. DT-diaphorase-deficient BE cells show markedly increased sensitivity to mitomycin C and particularly EO9 in hypoxic conditions, whereas DT-diaphorase-rich HT29 cells show little hypoxic sensitization to these agents unless exposed in the presence of dicoumarol. These results suggest that DT-diaphorase can reduce EO9 and mitomycin C to potent cytotoxic species in aerobic conditions, and this activity predominates over the one-electron-reducing enzymes even in hypoxic conditions. In the absence of DT-diaphorase activity, EO9 and mitomycin C are reduced in hypoxic conditions, presumably by one-electron-reducing enzymes, to a similar or greater extent than is achieved with DT-diaphorase.

Aerobiosis↗
PubMed1976

Phase II study of profiromycin vs mitomycin-C utilizing acute intermittent schedules.

A randomized prosective study of Mitomycin-C and its N-methyl derivative, Porfiromycin, was conducted. Thirty-two patients with disseminated gastrointestinal cancer or other disseminated abdominal adenocarcinoma were treated with Mitomycin-C; 31 patients received Porfiromycin. Both drugs were given by acute intermittent bolus schedule (Mitomucin-C , 22.5 mg/M2 or Porfiromycin, 75 mg/M2 every 6--8 weeks as a single bolus i.v. injection). Eleven patients (34%) who received Mitomycin-C entered into partial remission. In 10 of the 31 patients (32%) receiving Porfiromycin, partial remission occured. Analysis by tumor type demonstrated that in the Mitomycin-C treated group responses occured in 4 of 12 patients with colorectal carcinoma, in 4 of 9 with upper GI cancers, and in 3 of 11 with ovarian cancer. Correspondingly in Porfiromycin group responses occured in 2 of 12 colorectal carcinoma patients, in 3 of 7 upper GI cancer patients, and in 5 of 12 ovarian cancer patients. Both drugs produced significant myelosuppression; however, Porfiromycin toxicity appeared more cumulative. Further clinical trial of Mitomycin in an acute intermittent bolus schedule appears justified.

Abdominal Neoplasms↗
PubMed1996

On the nature of the adaptive response induced by mitomycin C in Vibrio cholerae OGAWA 154 cells.

The induction of an adaptive response in Vibrio cholerae OGAWA 154 cells was obtained using an alkylating agent, mitomycin C, as both stimulating and challenging agent. Cross-adaptive response was observed in V. cholerae cells when pretreated with a sublethal dose of another alkylating agent, N-methyl-N'nitro-N-nitrosoguanidine, followed by challenging treatment with mitomycin C. The dose of mitomycin C for 50% survival (D50) became almost double for mitomycin C pretreated cells and 1.5 times for N-methyl-N-'nitro-N-nitrosoguanidine pretreated cells, compared to nonpretreated cells. It was also shown that pretreatment with a sublethal dose of oxidative DNA damaging agents, viz, hydrogen peroxide or nitrofurantoin, did not show any cross-adaptive response against subsequent challenge by mitomycin C.

Acclimatization↗
PubMed1997

Effects of mitomycin C on the expression of proliferating cell nuclear antigen after filtering surgery in rabbits.

BACKGROUND: The aim of the study was to evaluate the effects of mitomycin C on the cell replication activity in wound healing following experimental filtration surgery. METHODS: Trabeculectomy with or without application of mitomycin C was performed on albino rabbit eyes. At 1, 4, 7, 14, and 28 days after surgery, the expression of proliferating cell nuclear antigen, a marker of cell proliferation, in the filtering site was examined immunohistochemically using a streptavidin-biotin complex method. RESULTS: In control eyes that underwent trabeculectomy but did not receive mitomycin C, the number of immunoreactive cells increased 4-7 days after operation and decreased markedly at around 14 days. The filtering site was obstructed histologically at 4-7 days after operation. In the mitomycin C-treated eyes, immunoreactive cells appeared 4 days after surgery but disappeared by 7 days at the surgical site. The number of immunoreactive cells in the treated eyes was much lower than that in control eyes. CONCLUSION: The cell replication activity was markedly inhibited by administration of mitomycin C. The filtering site remained open for 28 days after surgery, whereas it was completely obstructed within 7 days in control eyes. Immunocytochemistry for proliferating cell nuclear antigen, as used in this study, is a simple and reliable method for detection of cell replication activity.

Animals↗
PubMed1995

Mitomycin C and menadione for the treatment of advanced gastrointestinal cancers: a phase II trial.

A phase II trial of menadione (2.5 g/m2 as a continuous intravenous infusion over 48 h) followed by mitomycin C (10-20 mg/m2 i.v. bolus) administered every 4-6 weeks was performed in 43 patients with advanced gastrointestinal cancer. Menadione, a vitamin K analog that lowers intracellular pools of reduced glutathione, was combined with mitomycin C in an attempt to overcome thiol-mediated resistance to alkylating-agent chemotherapy. The median age of patients entered on this trial was 58 years; performance status ranged from 60%-100%. None of the 43 evaluable patients obtained an objective response to this combination regimen. Median survival was 6.6 months. Treatment with menadione and mitomycin C was reasonably well tolerated except for hematological toxicity. A total of 27% of treatment courses were complicated by grade 3 or 4 hematological toxicity including one episode of hemolytic anemia and one episode of hemolytic uremic syndrome. One patient developed irreversible interstitial pneumonitis, and 1 patient had an asymptomatic decrease in the left-ventricular ejection fraction. Despite preclinical evidence indicating that menadione pretreatment enhances the cytotoxicity of mitomycin C, our study documents the resistance of advanced gastrointestinal cancers, particularly colorectal cancer, to mitomycin C modulated by menadione.

Adult↗
PubMed1997

[Surgical revision for hypotonia after glaucoma operation with mitomycin C].

PURPOSE: Persistent hypotony with maculopathy is a severe complication of mitomycin C when used during filtration surgery. We wanted to know whether this complication can be controlled by a surgical reintervention yielding tight closure of the initial sclerostomy. METHOD: In our clinic, 52 eyes underwent filtering surgery with intraoperative application of mitomycin C. Seven of them required a reoperation owing to persistent hypotony with maculopathy. During this reoperation, the scleral flap was tightly sutured (5x) or, if necessary, was closed with dehydrated human dura mater (2x). RESULTS: In all cases the intraocular pressure increased immediately (i.e., within less than 24 h) after reoperation. This intraocular pressure increase was accompanied by a simultaneous regression of the maculopathy. Further details: mean intraocular pressure (mmHg): before initial operation with mitomycin C: 38.5 +/- 2.9; after initial operation: 3.7 +/- 0.6; before reoperation (= 8 months after initial operation): 3.3 +/- 0.7; 24 h after reoperation: 22.0 +/- 2.9; 9 months after reoperation: 16.7 +/- 1.7. Mean visual acuity: before initial operation with mitomycin C: 0.72 +/- 0.1; after initial operation: 0.34 +/- 0.1; before reoperation (= 8 months after initial operation): 0.17 +/- 0.05; 24 h after reoperation: 0.28 +/- 0.05; 9 months after reoperation: 0.55 +/- 0.1. CONCLUSIONS: (1) Since the interval between reoperation and intraocular pressure increase was very short in all cases, overfiltration is at least one major reason for hypotony, not only ciliary body failure; (2) in cases of persistent hypotony after filtering surgery with mitomycin C, surgical reintervation can be recommended. During this reoperation, the initial sclerostomy should be closed tightly.

Adult↗
PubMed2005

Tocotrienol inhibits proliferation of human Tenon's fibroblasts in vitro: a comparative study with vitamin E forms and mitomycin C.

PURPOSE: To evaluate the potential of the vitamin E compound alpha-tocotrienol as antifibrotic agent in vitro. METHODS: Using human Tenon's capsule fibroblast cultures, the antiproliferative and cytotoxic effects of the different vitamin E forms alpha-tocopherol, alpha-tocopheryl acetate, alpha-tocopheryl succinate and alpha-tocotrienol were compared with those of mitomycin C. To mimic subconjunctival and regular oral application in vivo, exposure time of serum-stimulated and serum-restimulated fibroblasts (SF and RF, respectively) to vitamin E forms was set at 6 days. Cultures were only exposed for 5 min to mitomycin C due to its known acute toxicity and to mimic the short-time intraoperative administration. Proliferation (expressed as % of control) was determined by DNA content quantification on days 2, 4 and 6, whereas cytotoxicity was assessed by cell morphology and glucose 6-phosphate dehydrogenase (G6PD) release after 24 h. RESULTS: alpha-Tocopherol and alpha-tocopheryl acetate stimulated growth of SF, but not RF. Reduction of fibroblast content by alpha-tocopheryl succinate was accompanied by increased G6PD release and necrosis. Contrary to alpha-tocopheryl succinate, 50 microM or repeatedly 20 microM of alpha-tocotrienol significantly inhibited proliferation without causing cellular toxicity (maximal effect: 46.8%). RF were more sensitive to this effect than SF. Mitomycin C 100-400 microg/ml showed a stronger antiproliferative effect than alpha-tocotrienol (maximal effect: 13.8%). Morphologic characteristics of apoptosis were more commonly found under treatment with mitomycin C. CONCLUSIONS: Of the vitamin E forms tested, only alpha-tocotrienol significantly inhibited growth at non-toxic concentrations. In this in vitro study, antiproliferative effects of mitomycin C were stronger than those of alpha-tocotrienol.

Aged↗
PubMed2005

Bullous keratopathy as a complication of trabeculectomy with mitomycin C.

BACKGROUND: The routine use of mitomycin C to enhance glaucomatous filtering surgery has found wide acceptance. Complications of the application of mitomycin C have been repeatedly noticed. We now report a previously undescribed complication showing a toxic effect of mitomycin C to the corneal endothelium. METHODS: Patients underwent routine trabeculectomy with mitomycin C. Following surgery, the eyes were examined by biomicroscopy and specular microscopy of the corneal endothelium. RESULTS: In two cases, we observed a partial decompensation of the corneal endothelium resulting in a well-demarcated clear zone of the cornea and a second zone with thickening of the cornea and a bullous keratopathy adjacent to the filtering bleb. The specular microscopy showed marked irregularities of the endothelial cells and areas of necrosis in those parts of the cornea close to the filtering bleb. CONCLUSIONS: The two cases described here demonstrate that if the corneal endothelium is already compromised before surgery, the application of mitomycin C may have an additional toxic effect on the endothelium and may result in a partial bullous keratopathy. Surgeons should be aware of this complication.

Adult↗
PubMed2005

Granulocyte macrophage-colony stimulating factor improves impaired anastomotic wound healing in rats treated with intraperitoneal mitomycin-C.

PURPOSE: Intraperitoneal chemotherapy (IPCT) delivers higher local concentrations of cytotoxic drugs than intravenous (i.v.) chemotherapy, but it can adversely affect the healing of intestinal anastomoses if given in the early postoperative period. Intestinal anastomotic leakage is a serious surgical complication. Experimental and clinical studies have shown that the local administration of granulocyte macrophage-colony stimulating factor (GM-CSF) improves would healing. Therefore, we evaluated the effects of locally applied GM-CSF on anastomotic wound healing in rats treated with intraperitoneal mitomycin-C immediately after surgery. METHODS: We performed colon anastomoses in albino rats, which were then divided into three treatment groups. Group A was a control group that received no treatment, Group B was given intraperitoneal mitomycin-C postoperatively, and Group C was given intraperitoneal mitomycin-C with a local injection of GM-CSF postoperatively. We measured bursting pressures and hydroxyproline content, and histologically examined the resected anastomoses on postoperative day (POD) 3. RESULTS: Anastomotic healing was impaired after intraperitoneal mitomycin-C, but this was overcome by the injection of GM-CSF into the perianastomotic area. CONCLUSION: Local GM-CSF administration counteracts the detrimental effects of intraperitoneal mitomycin-C treatment on intestinal anastomoses in rats.

Analysis of Variance↗
PubMed2004

Topical application of mitomycin C prevents epineural scar formation in rats.

The role of topically applied mitomycin C in preventing postoperative perineural fibrosis was examined by gross anatomical dissection and histological analysis in rats. The sciatic nerve was exposed bilaterally in 24 Wistar adult male rats, and an abrasion injury was produced on the exposed surface of the biceps femoris muscle in all animals. In the experimental group, cotton pads soaked with mitomycin C (0.5 mg/ml) were placed around the nerves for 5 min, whereas cotton pads soaked with saline were applied to the control group. Four weeks after surgery, the neurolysis sites were evaluated by blinded surgical dissection. Perineural adhesions were graded using a numerical grading scheme. The scar tissue formation index was also calculated, and a grading was made according to the number of fibroblasts/fibrocytes counted around the epineurium in histological evaluation. Mitomycin C-treated nerves showed significantly less perineural adhesions than controls. Quantification of the dense connective tissue surrounding the nerves revealed a statistically significant reduction around nerves treated with mitomycin C, and the number of fibroblast/fibrocytes was also significantly reduced. Application of topical mitomycin C might be effective in preventing epineural scar formation after neurolysis of peripheral nerves.

Administration, Topical↗
PubMed1996

Bioactivation of mitomycin antibiotics by aerobic and hypoxic Chinese hamster ovary cells overexpressing DT-diaphorase.

DT-Diaphorase catalyzes a two-electron reduction of mitomycin C (MC) and porfiromycin (POR) to reactive species. Many cell lines that overexpress DT-diaphorase and are sensitive to the mitomycins are protected from the aerobic cytotoxicity of these drugs by the DT-diaphorase inhibitor dicumarol. The cytoprotective properties of this relatively non-specific inhibitor, however, vanish under hypoxic conditions. To ascertain the role of DT-diaphorase in mitomycin bioactivation and cytotoxicity in living cells, a rat liver DT-diaphorase cDNA was transfected into Chinese hamster ovary cells. MC was equitoxic to the parental cells under oxygenated and hypoxic conditions. In contrast, POR was less toxic than MC to these cells under aerobic conditions, but significantly more toxic than MC under hypoxia. Two DT-diaphorase-transfected clones displayed increases in DT-diaphorase activity of 126- and 133-fold over parental cells. The activities of other oxidoreductases implicated in mitomycin bioreduction were unchanged. MC was more toxic to both DT-diaphorase-transfected lines than to parental cells; the toxicity of MC to the transfected lines was similar in air and hypoxia. POR was also more toxic to the DT-diaphorase-elevated clones than to parental cells under oxygenated conditions. Under hypoxia, however, the toxicity of POR to the transfected clones was unchanged from that of parental cells. The findings implicate DT-diaphorase in mitomycin bioactivation in living cells, but suggest that this enzyme does not contribute to the differential toxicity of MC or POR in air and hypoxia.

Animals↗